The present invention relates to a method of priming, enhancing and/or potentiating the effects of a vaccine using pretreatment with an antibody, including antibodies specific for the antigenic determinants from which the vaccine is derived.
The use of vaccines and vaccine compositions is presently a major method of dealing with the prevention and treatment of disease. However, because such vaccines and vaccine compositions incorporate whole proteins or polynucleotides or active fragments thereof, the effectiveness of such treatments can be highly variable. In some cases, highly purified proteins and polypeptides, and fragments thereof, incorporating antigenic determinants characteristic of a microorganism, such as a virus or bacterium, may fail to show sufficiently active protection against infection by said organism, possibly because of structural or steric shortcomings in the particular polypeptide or fragments used as the basis for the vaccine. Consequently, attempts have been made to enhance the effectiveness of such vaccines by addition of potentiating agents to the treatment process, especially in cases such as the treatment of a cancer where said cancer may show unexpectedly high sensitivity to the potentiating agent.
Heretofore, many different procedures have been developed to enhance the activity of vaccines and vaccine compositions by increasing the immunogenicity of such compositions. Part of the problem with such measures has been the hit or miss character of these procedures, many of which are based on just trial and error and are not otherwise carefully calculated to elicit the type of response desired and which makes the vaccine worthwhile. Among the more effective procedures has been the use of adjuvants (such as Freund""s complete adjuvant, although the latter is not useful in treating human patients) as well as the addition of simple organic molecules to the vaccine composition.
Many attempts at enhancing the immunogenicity of vaccines have revolved around extensive searches for small organic molecules that are effective, relatively non-toxic and economically advantageous to synthesize and utilize. Such efforts have met with only spotty success. Such compounds must, of course, be able to mimic the response with more complex immunogens, such as lipopolysaccharide of Escherichia coli and whole polypeptides used in immunogenic compositions. Some agents have shown promise, for example, the anti-tumor agent of U.S. Pat. No. 5,958,980.
Other approaches have involved forming particulate matter, such as by heat-induced aggregation of soluble antigens or by using self-aggregating antigenic particles (for example, the soluble antigen of hepatitis B virus possesses self-aggregation properties). Such particles have been found more useful in attracting immune cells such as macrophages and inducing immunity in the organism. Other attempts have employed more exotic structures such as liposomes, oily droplets, and alum precipitation.
Other methods of enhancing immunogenic activity of vaccines have included attempts to elicit an immunological reaction against an antigen administered along with a highly potent vaccine such that the latter provides a kind of adjuvant effect. For example, if a potent immunogen like killed Bordetella pertussis is administered along with a purified protein or polypeptide, the result is often a stronger immunogenic reaction to the purified protein or polypeptide, possibly due to the fact that the potent immunogen greatly stimulates the production of lymphokines, such as interleukin 4, that possess inter alia strong polyclonal activating activities.
Other methods have included such processes as slowing down the release of the immunogen so as to avoid activating suppressor pathways or avoiding direct intravenous administration, including subcutaneous devices to slowly release antigen.
Some methods have resorted to genetically engineering the organisms against which the immunogenic response is to be directed. For example, the vaccinia virus genome has been engineered to incorporate genes for various antigens of different pathogens. [See: Panicali and Paoletti, Proc. Natl. Acad. Sci USA, 79:4927 (1982); Smith et al, Nature, 302:490 (1983); Langford et al, Mol. Cell Biol., 6:3191 (1986); also see U.S. Pat. No. 5,879,685 for a highly descriptive survey of past methodologies] Other approaches have employed the use of surface active agents (such as saponin).
However, all of these methods have proven less than completely satisfactory because each has one or more disadvantages, mostly having to do with the eliciting of unwanted side reactions involving the stimulation of biological pathways within the recipient organism that can have a negative effect on the overall efficacy of the method being used. For example, alum precipitation often shows unwanted inflammatory effects. In addition, co-administration of antigen along with a potent immunogen is often useful only for a limited number of small peptides. Further, genetically engineering potentially dangerous microorganisms necessarily engenders safety concerns.
The present invention avoids these disadvantages by providing a means of potentiating, or enhancing, or priming the immunogenic effects of a vaccine, or vaccine composition, by utilizing a pretreatment step involving a highly specific and high affinity neutralizing antibody to prime the immunogenic reaction and thereby potentiate the effects of subsequent administration of the appropriate vaccine, or vaccine composition.
The present invention relates to a process for potentiating the immunogenic reaction of a given vaccine through pretreatment of an organism, such as a human patient, with a therapeutically effective amount of an antibody to prime response to the vaccine.
It is thus an object of the present invention to provide a method for enhancing the immunogenic activity of a vaccine, or vaccine composition, by first administering to an animal, such as a human patient, a therapeutically effective amount or dose of an antibody specific for an antigenic determinant of a cell or microorganism against which said animal is to be immunized, followed by administration to the same animal of an effective amount, or dose, of a vaccine, or vaccine composition, comprising at least one antigenic determinant for which the earlier administered antibody is specific.
It is another object of the present invention to provide a means of priming, or enhancing, or potentiating, the immunogenic activity of vaccines, and vaccine compositions, useful in immunizing against microorganisms, especially bacteria and viruses.
It is a further object of the present invention to provide a method for priming, enhancing or potentiating the immunogenic activity of vaccines, and vaccine compositions, useful in treating, and or preventing, diseases, especially where said disease afflicts a human patient, or where said human is at risk of contracting said disease. Among the diseases to be prevented or treated are those caused by bacteria and viruses, as well as chronic diseases, such as cancer.